We have utilized our in vitro and in vivo models of the multiple myeloma (MM) cell in the BM milieu to demonstrate the molecular mechanisms whereby novel agents target tumor cells, host interactions, and the BM microenvironment to overcome conventional drug resistance. We have then rapidly translated these laboratory findings to the clinic leading to FDA approvals of six novel treatments in the past five years; importantly, the median survival of MM patients has been extended from 3 to 7 years as a direct result of these advances. Our preclinical in vitro and in vivo efforts combining bortezomib with lenalidomide demonstrated synergistic MM cytotoxicity, and our derived clinical trials in newly diagnosed patients showed remarkable response; together, these data provided the rationale for the proposed clinical study in Project 1. We hypothesize that genetic changes identified using extensive oncogenomic profiling in Projects 2 and 4 represent novel therapeutic targets in MM. In this Project, we will use our robust human MM model systems to stringently validate the role of these novel targets in MM cell growth, survival, and drug resistance; and assess the therapeutic potential of these targets, both alone and in combination with established and emerging MM therapeutics. We will use a high-throughput shRNA-based assay directed at these targets to identify those regulating MM cell growth and survival in vitro (Specific Aim 1); validate the functional role of selected molecular targets regulating MM cell growth, survival, and drug resistance using our in vitro and in vivo models of human MM in the bone marrow milieu (Specific Aim 2); and evaluate the impact of potential therapeutic agents directed against these validated novel molecular targets, alone and in combination in MM (Specific Aim 3). This proposal will therefore identify the next generation of targeted therapies in MM.